STRUCTURE DETERMINATION OF MITONEET, A POTENTIAL TARGET FOR DIABETES INHIBITION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The rise in obesity in the United States parallels a dramatic increase in obesity-associated diseases, most notably type-2 diabetes. This disease is predicted to reach epidemic proportions in the next several decades. A drug of choice to treat type-II diabetes is pioglitazone, a thiazolidinedione (TZD) derivative originally thought to exert its effect through activation of the nuclear transcription factor PPAR. Recently, a novel protein target, mitoNEET, for pioglitazone was discovered. A soluble form of recombinant human mitoNEET was crystallized in an orthorhombic space group with unit-cell parameters a = 46.81 A, b = 49.62 A, c = 59.01 A. The structure was determined to 1.5 A resolution. Initial phasing was obtained from Fe-MAD datasets collected at wavelengths corresponding to the inflection, high energy remote, and absorption peak of Fe. Data was processed using automated MAD script developed at SSRL. The structural model was refined to an R-factor of 18.2 % and revealed a novel helical fold containing two 2Fe-2S binding domains 16 ¿ apart that are unusually labileThe protein mitoNEET may be involved with Fe-S cluster assembly or storage, binding transfer clusters that cross outer cell membranes.